Skeletal muscle possesses the ability to regenerate after injury and grow postnatally through the activation of satellite cells. The molecular mechanisms which control satellite cell function are not completely understood. Recently, it has been revealed that microRNAs (miRNAs), which negatively regulate gene expression by promoting mRNA degradation and inhibiting mRNA translation, function in the stress response of muscle cells and play important roles in muscle development and disease. We have identified 9 miRNAs which are up-regulated after cardiotoxin-induced skeletal muscle injury and 20 which are down-regulated. We plan to investigate the role of a number of these miRNAs in the regenerative process. To achieve this goal we will use in vitro approaches in conjunction with knockout and transgenic mouse models. In particular, we will focus on the role of the dramatically induced miR-206 (16-fold increase after cardiotoxin injury) in skeletal muscle regeneration and remodeling. miR-206 knockout mice have been generated, are viable, and exhibit no gross abnormalities in skeletal muscle. Using these mutant mice we will assess the role of miR-206 in regeneration and elucidate the downstream effectors which mediate this response. These studies will provide new insights into the pathophysiology of muscle disease and regeneration, and should also facilitate the development of new therapeutic strategies for muscle repair through the manipulation of miRNA expression and function. PUBLIC HEALTH RELEVANCE: The overall aim of this project is to elucidate the mechanisms that regulate microRNA-206 expression in response to injury and regeneration and to define the targets of miR-206 that mediate these processes. These studies will provide new insights into the pathophysiology of muscle disease and regeneration, and should also facilitate the development of new therapeutic strategies for muscle repair through the manipulation of miRNA expression and function.